Project Summary Cocaine addiction is a chronic, relapsing disease that has resisted prevention efforts and for which there are no approved pharmacotherapies. Despite considerable effort to identify the factors that predict the vulnerability to develop cocaine addiction, the mechanisms that predispose individuals to addiction remain poorly understood. An extensive body of research implicates the mesolimbic dopamine system in the reinforcing effects of cocaine, where cocaine acts to increase extrasynaptic dopamine primarily through inhibition of the dopamine transporter. Recent evidence suggests that variability in dopamine transporter function may influence the risk for developing cocaine addiction. For example, rats with high novelty-induced locomotion have a greater propensity to self-administer cocaine, and display exaggerated dopamine responses to cocaine. Moreover, rats exposed to a social stressor believed to be associated with risk for substance abuse have enhanced dopamine uptake rates and consume more cocaine in adulthood. While these reports suggest a dopamine transporter involvement in the risk for cocaine addiction the existence, magnitude, and direction of this relationship remains unclear. Thus, to further examine whether the risk of cocaine addiction is linked to intrinsic, individual differences in dopamine neurotransmission, we employ a novel approach using fast scan cyclic voltammetry to construct a neurochemical profile of dopamine release and uptake in individual rats under baseline, drug-nave conditions prior to initiation of cocaine self-administration. We will examine dopamine neurotransmission in the medial caudate based on preliminary observations indicating that dopamine uptake rates in this region robustly predict the motivation for cocaine. Using cutting-edge neurochemical techniques and sophisticated, well-established behavioral assays, we will: 1) determine the contribution of specific aspects of dopamine neurotransmission to cocaine reward, motivation, extinction, and relapse; and 2) use viral manipulations to overexpress or knockdown dopamine transporters in the medial caudate to evaluate the causative role of dopamine transporter function in cocaine self-administration. Completion of these studies will provide important insight into the role of dopamine neurotransmission in the risk for cocaine abuse and will provide important information into potential targets for future preventative and/or therapeutic interventions for addiction.